St. Jude Reference #SJ-21-0001
Description
Researchers at St. Jude have developed proteolysis targeting chimeras (PROTACs) aimed at inducing PXR degradation. Conjugation of a SPA70 derivative to ligands of the E3 substrate receptor cereblon (CRBN) resulted in one molecule, SJPYT-195, that reduced PXR protein level in an optimized degradation assay described here. Further analysis revealed that SJPYT-195 was a molecular glue degrader of the translation termination factor GSPT1 and that GSPT1 degradation resulted in subsequent reduction of PXR protein. GSPT1 has recently gained interest as an anticancer target, and our results give new insights into chemical determinants of drug-induced GSPT1 degradation. Additionally, they developed assays and cell models for PXR degrader discovery that can be applied to additional protein targets; and they discovered a compound that failed to directly degrade PXR, which degrades GSPT1, possibly affecting tumors such as in acute myeloid leukemia (AML).
These compounds can be used for GSPT1 degradation. Although GSPT1 degraders exist, SJPYT-195 is structurally unique. The GSPT1 degrader can produce drugs for cancer chemotherapies. SJPYT-231 is a high affinity binder of cereblon which is valuable for future development of protein degraders.
Keywords
PROTAC, molecular glue, pregnane X receptor, GSPT1, acute myeloid leukemia, cancer
Granted Patents or Published Applications
A provisional patent application has been filed.
Related Scientific References
Andrew D. Huber, Yongtao Li, Wenwei Lin, Annalise N. Galbraith, Ashutosh Mishra, Shaina N. Porter, Jing Wu, Rebecca R. Florke Gee, Wei Zhuang, Shondra M. Pruett-Miller, Junmin Peng, and Taosheng Chen; “SJPYT-195: A Designed Nuclear Receptor Degrader That Functions as a Molecular Glue Degrader of GSPT1;” ACS Medicinal Chemistry Letters 2022 13 (8), 1311-1320. DOI: 10.1021/acsmedchemlett.2c00223
Li Y, Lin W, Chai SC, Wu J, Annu K, Chen T., “Design and Optimization of 1H-1,2,3-Triazole-4-carboxamides as Novel, Potent, and Selective Inverse Agonists and Antagonists of PXR.” J Med Chem. 2022 Dec 22;65(24):16829-16859.
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